tbuckley/cabot-search huggingface dataset:
Dysfunctional Coupling of Cerebral Blood Flow and Susceptibility Value in the Bilateral Hippocampus is Associated with Cognitive Decline in Nondialysis Patients with CKD
Authors: Hao Wang, Xu Liu, Lijun Song, Wenbo Yang, Mingan Li, Qian Chen, Han Lv, Pengfei Zhao, Zhenghan Yang, Wenhu Liu, Zhen-chang Wang
Journal: Journal of the American Society of Nephrology (2023)

Patients with end stage CKD often develop cognitive decline, but whether this is related to the underlying disease or to hemodialysis remains unclear. We performed three-dimensional pseudocontinuous arterial spin labeling and quantitative susceptibility mapping prospectively in 40 patients with stage 1-4 CKD, 47 nondialysis patients with stage 5 CKD, and 44 healthy controls. Our magnetic resonance imaging data demonstrate that changes in cerebral blood flow-susceptibility coupling might underlie this cognitive decline, perhaps in the hippocampus and thalamus. These results suggest that magnetic resonance imaging parameters are potential biomarkers of cognitive decline in patients with CKD. Moreover, our findings may lead to discovery of novel therapeutic targets to prevent cognitive decline in patients with CKD.
Single-Cell Characterization of Pulmonary Nodules Implicates Suppression of Immunosurveillance across Early Stages of Lung Adenocarcinoma
Authors: Jane Yanagawa, Linh M. Tran, Ramin Salehi-Rad, Raymond J. Lim, Camelia Dumitras, Eileen Fung, William D. Wallace, Ashley E. Prosper, Gregory Fishbein, Conor Shea, Rui Hong, Bitta Kahangi, John J. Deng, Adam C. Gower, Bin Liu, Joshua D. Campbell, Sarah A. Mazzilli, Jennifer E. Beane, Humam Kadara, Marc E. Lenburg, Avrum E. Spira, Denise R. Aberle, Kostyantyn Krysan, Steven M. Dubinett
Journal: Cancer Research (2023)

A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmonary nodules representing the spectrum of early lung adenocarcinoma as well as associated normal lung tissues using single-cell RNA sequencing and validated the results by flow cytometry and multiplex immunofluorescence (MIF). Single-cell transcriptomics revealed a significant decrease in gene expression associated with cytolytic activities of tumor-infiltrating natural killer and natural killer T cells. This was accompanied by a reduction in effector T cells and an increase of CD4+ regulatory T cells (Treg) in subsolid nodules. An independent set of resected pulmonary nodules consisting of both adenocarcinomas and associated premalignant lesions corroborated the early increment of Tregs in premalignant lesions compared with the associated normal lung tissues by MIF. Gene expression analysis indicated that cancer-associated alveolar type 2 cells and fibroblasts may contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid nodules through ligand-receptor interactions. These findings suggest that there is a suppression of immune surveillance across the spectrum of early-stage lung adenocarcinoma.
Transplantation of gut microbiota from old mice into young healthy mice reduces lean mass but not bone mass
Authors: Lina Lawenius, Carrie Cowardin, Louise Grahnemo, Julia M. Scheffler, Karin Horkeby, Cecilia Engdahl, Jianyao Wu, Liesbeth Vandenput, Antti Koskela, Juha Tuukkanen, Eivind Coward, Kristian Hveem, Arnulf Langhammer, Sanna Abrahamsson, Jeffrey I. Gordon, Klara Sjögren, Claes Ohlsson
Journal: Gut Microbes (2023)

Aging is associated with low bone and lean mass as well as alterations in the gut microbiota (GM). In this study, we determined whether the reduced bone mass and relative lean mass observed in old mice could be transferred to healthy young mice by GM transplantation (GMT). GM from old (21-month-old) and young adult (5-month-old) donors was used to colonize germ-free (GF) mice in three separate studies involving still growing 5- or 11-week-old recipients and 17-week-old recipients with minimal bone growth. The GM of the recipient mice was similar to that of the donors, demonstrating successful GMT. GM from old mice did not have statistically significant effects on bone mass or bone strength, but significantly reduced the lean mass percentage of still growing recipient mice when compared with recipients of GM from young adult mice. The levels of propionate in the cecum of mice receiving old donor GM were significantly lower than those in mice receiving young adult donor GM. Bacteroides ovatus was enriched in the microbiota of recipient mice harboring GM from young adult donors. The presence of B. ovatus was not only significantly associated with high lean mass percentage in mice, but also with lean mass adjusted for fat mass in the large human HUNT cohort. In conclusion, GM from old mice reduces lean mass percentage but not bone mass in young, healthy, still growing recipient mice. Future studies are warranted to determine whether GM from young mice improves the musculoskeletal phenotype of frail elderly recipient mice.
Trends in the Use of Mifepristone for Medical Management of Early Pregnancy Loss From 2016 to 2020
Authors: Elise W. Boos, Manuel Horta, Ivana Thompson, Stacie B. Dusetzina, Ashley A. Leech
Journal: JAMA (2023)

This study assesses the use of mifepristone plus misoprostol for miscarriage management among commercially insured adults in the US.
Integrated molecular analysis reveals hypermethylation and overexpression of HOX genes to be poor prognosticators in isocitrate dehydrogenase mutant glioma
Authors: Yasin Mamatjan, Mathew R Voisin, Farshad Nassiri, Fabio Y Moraes, Severa Bunda, Jonathan So, Mira Salih, Mitsuaki Shirahata, Takahiro Ono, Hiroaki Shimizu, Daniel Schrimpf, Andreas von Deimling, Kenneth D Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2023)

Abstract Background Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within isocitrate dehydrogenase (IDH)-mutant gliomas, there is a high variability in survival and a need to more accurately predict outcome. Methods To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV), and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and 2 validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA). Results Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into 2 prognostic groups strongly predicting survival that were validated using 2 independent cohorts from TCGA and DKFZ (all P-values &amp;lt; .0001). The methylation signatures that predicted poor outcomes also exhibited high CNV instability and hypermethylation of HOX gene probes. Integrated multi-platform analyses using mRNA and methylation (iRM) showed that parallel HOX gene overexpression and simultaneous hypermethylation were significantly associated with increased mutational load, high aneuploidy, and worse survival (P-value &amp;lt; .0001). A 7-HOX gene signature was developed and validated using the most significantly associated HOX genes with patient outcome in both 1p/19q codeleted and non-codeleted IDHmut gliomas. Conclusions HOX gene methylation and expression provide important prognostic information in IDH-mutant gliomas that are not captured by current molecular diagnostics. A 7-HOX gene signature of outcome shows significant survival differences in both 1p/19q codeleted and non-codeleted IDH-mutant gliomas.
Use of Respiratory Syncytial Virus Vaccines in Older Adults: Recommendations of the Advisory Committee on Immunization Practices — United States, 2023
Authors: Michael Melgar, Amadea Britton, Lauren E. Roper, H. Keipp Talbot, Sarah S. Long, Camille N. Kotton, Fiona P. Havers
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Respiratory syncytial virus (RSV) is a cause of severe respiratory illness in older adults. In May 2023, the Food and Drug Administration approved the first vaccines for prevention of RSV-associated lower respiratory tract disease in adults aged ≥60 years. Since May 2022, the Advisory Committee on Immunization Practices (ACIP) Respiratory Syncytial Virus Vaccines Adult Work Group met at least monthly to review available evidence regarding the safety, immunogenicity, and efficacy of these vaccines among adults aged ≥60 years. On June 21, 2023, ACIP voted to recommend that adults aged ≥60 years may receive a single dose of an RSV vaccine, using shared clinical decision-making. This report summarizes the body of evidence considered for this recommendation and provides clinical guidance for the use of RSV vaccines in adults aged ≥60 years. RSV vaccines have demonstrated moderate to high efficacy in preventing RSV-associated lower respiratory tract disease and have the potential to prevent substantial morbidity and mortality among older adults; postmarketing surveillance will direct future guidance.
The RNA binding proteins TIA1 and TIAL1 promote Mcl1 mRNA translation to protect germinal center responses from apoptosis
Authors: Ines C. Osma-Garcia, Mailys Mouysset, Dunja Capitan-Sobrino, Yann Aubert, Martin Turner, Manuel D. Diaz-Muñoz
Journal: Cellular and Molecular Immunology (2023)

Germinal centers (GCs) are essential for the establishment of long-lasting antibody responses. GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into functional changes in the cell proteome. However, the critical proteins driving these key mechanisms are still unknown. Here, we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses. TIA1- and TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection, expansion and differentiation into B-cell clones producing high-affinity antibodies. Mechanistically, TIA1 and TIAL1 control the transcriptional identity of dark- and light-zone GC B cells and enable timely expression of the prosurvival molecule MCL1. Thus, we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.
Prevalence of Low-Frequency, Antiviral Resistance Variants in SARS-CoV-2 Isolates in Ontario, Canada, 2020-2023
Authors: Calvin P. Sjaarda, Lynette Lau, Jared T. Simpson, Ramzi Fattouh, Mia J. Biondi, Finlay Maguire, Aaron Campigotto, Yujia Feng, Kyla Tozer, Henry Wong, Wilson W. L. Sung, Sean Kim, Christian R. Marshall, Prameet M. Sheth, Robert Kozak
Journal: JAMA Network Open (2023)

Nirmatrelvir-ritonavir is an oral antiviral medication that improves outcomes in SARS-CoV-2 infections. However, there is concern that antiviral resistance will develop and that these viruses could be selected for after treatment.To determine the prevalence of low-frequency SARS-CoV-2 variants in patient samples that could be selected for by nirmatrelvir-ritonavir.This retrospective cohort study was conducted at 4 laboratories that serve community hospitals, academic tertiary care centers, and COVID-19 assessment centers in Ontario, Canada. Participants included symptomatic or asymptomatic patients who tested positive for SARS-CoV-2 virus and submitted virus samples for diagnostic testing between March 2020 and January 2023.SARS-CoV-2 infection.Samples with sufficient viral load underwent next-generation genome sequencing to identify low-frequency antiviral resistance variants that could not be identified through conventional sequencing.This study included 78 866 clinical samples with next-generation whole-genome sequencing data for SARS-CoV-2. Low-frequency variants in the viral nsp5 gene were identified in 128 isolates (0.16%), and no single variant associated with antiviral resistance was predominate.This cohort study of low-frequency variants resistant to nirmatrelvir-ritonavir found that these variants were very rare in samples from patients with SARS-CoV-2, suggesting that selection of these variants by nirmatrelvir-ritonavir following the initiation of treatment may also be rare. Surveillance efforts that involve sequencing of viral isolates should continue to monitor for novel resistance variants as nirmatrelvir-ritonavir is used more broadly.
Single-cell transcriptome analysis profiles cellular and molecular alterations in submandibular gland and blood in IgG4-related disease
Authors: Yanmei Li, Zhiqin Wang, Feng Han, Mei Zhang, Tong Yang, Ming Chen, Jun Du, Yin Wang, Li Zhu, Hou Hou, Yanxia Chang, Lin Han, Xing Lyu, Na Zhang, Wenwen Sun, Zhigang Cai, Wei Wei
Journal: Annals of the Rheumatic Diseases (2023)

The aim of this study is to profile the transcriptional landscapes of affected tissues and peripheral blood mononuclear cells (PBMCs) at the single-cell level in IgG4-related disease (IgG4-RD). Identifying the cell populations and crosstalk between immune cells and non-immune cells will assist us in understanding the aetiology of IgG4-RD.We performed single-cell RNA sequencing analysis on submandibular glands (SMGs) and PBMCs from patients with IgG4-RD and matched controls. Additionally, bulk RNA sequencing of PBMCs was used to construct the immune repertoire. Furthermore, multiplex immunofluorescence staining was performed to validate the transcriptomic results.We identified three novel subsets of tissue-resident immune cells in the SMGs of patients with IgG4-RD. TOP2A_B cells and TOP2A_T cells had stemness signatures, and trajectory analysis showed that TOP2A_B cells may differentiate into IgG4+plasma cells and that TOP2A_T cells may differentiate into T follicular helper (Tfh) cells. ICOS_PD-1_B cells with Tfh-like characteristics appeared to be an intermediate state in the differentiation from B cells to IgG4+plasma cells. The cellular communication patterns within immune cells and between immune cells and non-immune cells were altered in IgG4-RD compared with controls. Consistently, infection-related pathways were shared in B cells and T cells from SMGs and PBMCs. Furthermore, immune clonotype analysis of PBMC samples showed the complementary determining region 3 amino acid CQQSYSTPYTF was expanded in patients with IgG4-RD.Our data revealed the cellular and molecular changes at the single-cell resolution of IgG4-RD and provide valuable insights into the aetiology and novel therapeutic targets of the autoimmune disease.
A Phase II Study of Optimized Individualized Adaptive Radiotherapy for Hepatocellular Carcinoma
Authors: Daniel J. Herr, Chang Wang, Mishal Mendiratta-Lala, Martha Matuszak, Charles S. Mayo, Yue Cao, Neehar D. Parikh, Randy Ten Haken, Dawn Owen, Joseph R. Evans, Teodor Stanescu, Michael Yan, Laura A. Dawson, Matthew Schipper, Theodore S. Lawrence, Kyle C. Cuneo
Journal: Clinical Cancer Research (2023)

Abstract Purpose: We hypothesized that optimizing the utility of stereotactic body radiotherapy (SBRT) based on the individual patient's probability for tumor control and risk of liver injury would decrease toxicity without sacrificing local control in patients with impaired liver function or tumors not amenable to thermal ablation. Patients and Methods: Patients with Child-Pugh (CP) A to B7 liver function with aggregate tumor size &amp;gt;3.5 cm, or CP ≥ B8 with any size tumor were prospectively enrolled on an Institutional Review Board–approved phase II clinical trial to undergo SBRT with baseline and midtreatment dose optimization using a quantitative, individualized utility-based analysis. Primary endpoints were change in CP score of ≥2 points within 6 months and local control. Protocol-treated patients were compared with patients receiving conventional SBRT at another cancer center using overlap weighting. Results: A total of 56 patients with 80 treated tumors were analyzed with a median follow-up of 11.2 months. Two-year cumulative incidence of local progression was 6.4% [95% confidence interval (CI, 2.4–13.4)]. Twenty-one percent of patients experienced treatment-related toxicity within 6 months, which is similar to the rate for SBRT in patients with CP A liver function. An analysis using overlap weighting revealed similar local control [HR, 0.69; 95% CI (0.25–1.91); P = 0.48] and decreased toxicity [OR, 0.26; 95% CI (0.07–0.99); P = 0.048] compared with conventional SBRT. Conclusions: Treatment of individuals with impaired liver function or tumors not amenable to thermal ablation with a treatment paradigm designed to optimize utility may decrease treatment-related toxicity while maintaining tumor control.
Promoting early childhood development in Viet Nam: cost-effectiveness analysis alongside a cluster-randomised trial
Authors: Yeji Baek, Zanfina Ademi, Thach Tran, Alice Owen, Trang Nguyen, Stanley Luchters, David B Hipgrave, Sarah Hanieh, Tuan Tran, Ha Tran, Beverley-Ann Biggs, Jane Fisher
Journal: The Lancet Global Health (2023)

BackgroundEconomic evaluations are critical to ensure effective resource use to implement and scale up child development interventions. This study aimed to estimate the cost-effectiveness of a multicomponent early childhood development intervention in rural Viet Nam.MethodsWe did a cost-effectiveness study alongside a cluster-randomised trial with a 30-month time horizon. The study included 669 mothers from 42 communes in the intervention group, and 576 mothers from 42 communes in the control group. Mothers in the intervention group attended Learning Clubs sessions from mid-pregnancy to 12 months after delivery. The primary outcomes were child cognitive, language, motor, and social–emotional development at age 2 years. In this analysis, we estimated the incremental cost-effectiveness ratios (ICERs) of the intervention compared with the usual standard of care from the service provider and household perspectives. We used non-parametric bootstrapping to examine uncertainty, and applied a 3% discount rate.FindingsThe total intervention cost was US$169 898 (start-up cost $133 692 and recurrent cost $36 206). The recurrent cost per child was $58 (1 341 741 Vietnamese dong). Considering the recurrent cost alone, the base-case ICER was $14 and mean ICER of 1000 bootstrap samples was $14 (95% CI –0·48 to 30) per cognitive development score gained with a 3% discount rate to costs. The ICER per language and motor development score gained was $22 and $20, respectively, with a 3% discount rate to costs.InterpretationThe intervention was cost-effective: the ICER per child cognitive development score gained was 0·5% of Viet Nam's gross domestic product per capita, alongside other benefits in language and motor development. This finding supports the scaling up of this intervention in similar socioeconomic settings.FundingAustralian National Health and Medical Research Council and Grand Challenges Canada.TranslationFor the Vietnamese translation of the abstract see Supplementary Materials section.
A machine learning based approach to identify carotid subclinical atherosclerosis endotypes
Authors: Qiao Sen Chen, Otto Bergman, Louise Ziegler, Damiano Baldassarre, Fabrizio Veglia, Elena Tremoli, Rona J Strawbridge, Antonio Gallo, Matteo Pirro, Andries J Smit, Sudhir Kurl, Kai Savonen, Lars Lind, Per Eriksson, Bruna Gigante
Journal: Cardiovascular Research (2023)

Abstract Aims To define endotypes of carotid subclinical atherosclerosis. Methods and results We integrated demographic, clinical, and molecular data (n = 124) with ultrasonographic carotid measurements from study participants in the IMPROVE cohort (n = 3340). We applied a neural network algorithm and hierarchical clustering to identify carotid atherosclerosis endotypes. A measure of carotid subclinical atherosclerosis, the c-IMTmean-max, was used to extract atherosclerosis-related features and SHapley Additive exPlanations (SHAP) to reveal endotypes. The association of endotypes with carotid ultrasonographic measurements at baseline, after 30 months, and with the 3-year atherosclerotic cardiovascular disease (ASCVD) risk was estimated by linear (β, SE) and Cox [hazard ratio (HR), 95% confidence interval (CI)] regression models. Crude estimates were adjusted by common cardiovascular risk factors, and baseline ultrasonographic measures. Improvement in ASCVD risk prediction was evaluated by C-statistic and by net reclassification improvement with reference to SCORE2, c-IMTmean-max, and presence of carotid plaques. An ensemble stacking model was used to predict endotypes in an independent validation cohort, the PIVUS (n = 1061). We identified four endotypes able to differentiate carotid atherosclerosis risk profiles from mild (endotype 1) to severe (endotype 4). SHAP identified endotype-shared variables (age, biological sex, and systolic blood pressure) and endotype-specific biomarkers. In the IMPROVE, as compared to endotype 1, endotype 4 associated with the thickest c-IMT at baseline (β, SE) 0.36 (0.014), the highest number of plaques 1.65 (0.075), the fastest c-IMT progression 0.06 (0.013), and the highest ASCVD risk (HR, 95% CI) (1.95, 1.18–3.23). Baseline and progression measures of carotid subclinical atherosclerosis and ASCVD risk were associated with the predicted endotypes in the PIVUS. Endotypes consistently improved measures of ASCVD risk discrimination and reclassification in both study populations. Conclusions We report four replicable subclinical carotid atherosclerosis—endotypes associated with progression of atherosclerosis and ASCVD risk in two independent populations. Our approach based on endotypes can be applied for precision medicine in ASCVD prevention.
Is this pill an antibiotic or a painkiller? Improving the identification of oral antibiotics for better use
Authors: Annelie A Monnier, Nga T T Do, Kwaku Poku Asante, Samuel Afari-Asiedu, Wasif Ali Khan, Khátia Munguambe, Esperanca Sevene, Toan K Tran, Chuc T K Nguyen, Sureeporn Punpuing, F Xavier Gómez-Olivé, H Rogier van Doorn, Céline Caillet, Paul N Newton, Proochista Ariana, Heiman F L Wertheim, Heiman FL Wertheim, Annelie A Monnier, Paul N Newton, Céline Caillet, Proochista Ariana, Taniya Sharmeen, Kwaku Poku Asante, Samuel Afari-Asiedu, Khátia Munguambe, Esperanca Sevene, Helena Boene, Wasif Ali Khan, Mohammed Abdul Matin, Toan K Tran, Chuc T K Nguyen, Tuyet A Phuong, Sureeporn Punpuing, Malee Sunpuwan, Wipaporn Jarruruengpaisan, F Xavier Gómez-Olivé, Georgina Pujol-Busquets Guillén, Sizzy Ngobeni, Floidy Wafawanaka, Nga T T Do, H Rogier van Doorn
Journal: The Lancet Global Health (2023)

In this Viewpoint, we discuss how the identification of oral antibiotics and their distinction from other commonly used medicines can be challenging for consumers, suppliers, and health-care professionals. There is a large variation in the names that people use to refer to antibiotics and these often relate to their physical appearance, although antibiotics come in many different physical presentations. We also reflect on how the physical appearance of medicine influences health care and public health by affecting communication between patients and health-care professionals, dispensing , medicine use, and the public understanding of health campaigns. Furthermore, we report expert and stakeholder consultations on improving the identification of oral antibiotics and discuss next steps towards a new identification system for antibiotics. We propose to use the physical appearance as a tool to support and nudge awareness about antibiotics and their responsible use.